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Biochem J. 2004 Aug 15;382(Pt 1):239-45.

Functional analysis of peroxisome-proliferator-responsive element motifs in genes of fatty acid-binding proteins.

Author information

1
Department of Biochemistry, University of Münster, Wilhelm-Klemm-Str. 2, 48149 Münster, Germany.

Abstract

Retinoic acids and long-chain fatty acids are lipophilic agonists of nuclear receptors such as RXRs (retinoic X receptors) and PPARs (peroxisome-proliferator-activated receptors) respectively. These agonists are also ligands of intracellular lipid-binding proteins, which include FABPs (fatty acid-binding proteins). We reported previously that L (liver-type)-FABP targets fatty acids to the nucleus of hepatocytes and affects PPARalpha activation, which binds together with an RXR subtype to a PPRE (peroxisome-proliferator-responsive element). In the present study, we first determined the optimal combination of murine PPAR/RXR subtypes for binding to known murine FABP-PPREs and to those found by computer search and then tested their in vitro functionality. We show that all PPARs bind to L-FABP-PPRE, PPARalpha, PPARgamma1 and PPARgamma2 to A (adipocyte-type)-FABP-PPRE. All PPAR/RXR heterodimers transactivate L-FABP-PPRE, best are combinations of PPARalpha with RXRalpha or RXRgamma. In contrast, PPARalpha heterodimers do not transactivate A-FABP-PPRE, best combinations are of PPARgamma1 with RXRalpha and RXRgamma, and of PPARgamma2 with all RXR subtypes. We found that the predicted E (epidermal-type)- and H (heart-type)-FABP-PPREs are not activated by any PPAR/RXR combination without or with the PPAR pan-agonist bezafibrate. In the same way, C2C12 myoblasts transfected with promoter fragments of E-FABP and H-FABP genes containing putative PPREs are also not activated through stimulation of PPARs with bezafibrate applied to the cells. These results demonstrate that only PPREs of L- and A-FABP promoters are functional, and that binding of PPAR/RXR heterodimers to a PPRE in vitro does not necessarily predict transactivation.

PMID:
15130092
PMCID:
PMC1133936
DOI:
10.1042/BJ20031340
[Indexed for MEDLINE]
Free PMC Article

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